Birth defects, which affect three of every 100 babies born in the US, are a leading cause of infant mortality both nationally and globally and can cause continuing morbidity for infants who survive. Despite the significance of this public health problem, clinical and public health efforts to prevent most birth defects simply do not exist. A major barrier to establishing prevention programs is the lack of evidence regarding etiology of most nonsyndromic birth defects. The National Birth Defects Prevention Study (NBDPS) was launched in 1997 to investigate the complex etiology of more than 30 major nonsyndromic birth defects. As part of the NBDPS, the Arkansas Center for Birth Defects Research and Prevention is dedicated to understanding the causes of birth defects and contributing to an evidence base that facilitates development of effective prevention strategies. The Center's long-term goal is to prevent or significantly reduce the occurrence of birth defects. Participating in NBDPS has provided the Arkansas Center with an irreplaceable repository of information regarding maternal exposures and lifestyle factors that may be associated with birth defects and valuable DNA samples from a large population-based sample. Continued support from CDC will sustain Arkansas' impressive participation in NBDPS, help the Center continue to generate cutting-edge research and to share research results, and leverage CDC support to gain support for birth defect research at the local level. In the upcoming funding cycle, the Arkansas Center will expand its existing research efforts to address birth defects through three specific aims: continue participation in the National Birth Defects Prevention Study and in so doing expand the epidemiological research capacity of the Arkansas Center (Aim 1); continue to conduct local and collaborative studies that investigate the complex etiology of birth defects by utilizing data from the Arkansas Reproductive Health Monitoring System and NBDPS (Aim 2), and continue to support highthroughput genomic and epigenomic analyses of biological samples collected from NBDPS participants by augmenting CDC support with institutional and extramural funds (Aim 3). These aims will be achieved by addressing epigenetic mechanisms (altered gene-specific methylation), genetic susceptibilities (single nucleotide polymorphisms), pro-oxidant lifestyle factors (smoking, alcohol, obesity), maternal nutrition (e.g., low dietary folate), and maternal innate immunity (impaired function in immune response genes). Project outcomes will be immediate, direct contributions to the understanding of genetic, environmental, and metabolic causes of birth defects and the necessary foundation for clinical and public health primary prevention programs. The convergence of the National Birth Defects Prevention Study, advances in genomic tools, and leading multidisciplinary expertise promises to produce an evidence-base that can be the basis of primary prevention programs.